Al Saad, Sarah
(2022)
The Role of SAHA in Attenuating Liver Fibrosis.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Chronic liver disease (CLD) is one of the leading causes of morbidity and mortality globally. There are approximately 1.5 billion cases of CLD worldwide, with 4.5 million cases in the United States alone. Most types of CLD are a result of a wound healing process that leads to extracellular matrix deposition and scar tissue formation, or liver fibrosis. When left untreated, liver fibrosis may progress to cirrhosis or hepatocellular carcinoma, and ultimately liver failure, thereby requiring liver transplantation. Unfortunately, the only treatment available for liver fibrosis is removal of the causative agent. This highlights the importance of finding novel therapeutic targets and repurposing drugs to treat liver fibrosis. Histone deacetylase inhibitors (HDACi) have been reported to be beneficial in diseases of fibrosis. Vorinostat, or suberoylanilide hydroxamic acid (SAHA), a pan HDACi used to treat T-cell lymphoma, was reported to inhibit hepatic stellate cell activation and liver fibrosis. However, the mechanism behind this attenuation has yet to be explored in detail. We previously published that overexpression of a redox regulator, Glutaredoxin-1 (Glrx) is protective in liver fibrosis. Therefore, I investigated whether SAHA inhibits hepatic stellate cell activation by upregulating Glrx. I first confirmed SAHA’s inhibition of both human and mouse hepatic stellate cell activation and attenuation of liver fibrosis in a carbon tetrachloride mouse model. SAHA also significantly upregulated the expression of Glrx in both mouse and human hepatic stellate cells. Knockdown of GLRX partially attenuated SAHA’s inhibitory effect on HSC activation. Based on these results, I conclude that SAHA’s inhibition of hepatic stellate cell activation may be Glrx-dependent.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| Contributors: |
| Contribution | Contributors Name | Email | Pitt Username | ORCID  |
|---|
| Committee Chair | Xie, Wen | wex6@pitt.edu | wex6 | UNSPECIFIED | | Committee Member | Ma, Xiaochao | MXIAOCHA@pitt.edu | MXIAOCHA | UNSPECIFIED | | Committee Member | Yang, Da | dyang@pitt.edu | dyang | UNSPECIFIED |
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| ETD Committee: |
|
| Date: |
7 April 2022 |
| Date Type: |
Submission |
| Defense Date: |
5 April 2022 |
| Approval Date: |
8 April 2022 |
| Submission Date: |
8 April 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
40 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
No |
| Uncontrolled Keywords: |
SAHA, Glutaredoxin-1, hepatic stellate cells, liver fibrosis |
| Date Deposited: |
08 Apr 2022 18:46 |
| Last Modified: |
14 Nov 2024 19:14 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42536 |
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